Lipid-modifying efficacy and tolerability of anacetrapib added to ongoing statin therapy in Japanese patients with dyslipidemia

Teramoto, Tamio; Daida, Hiroyuki; Ikewaki, Katsunori; Arai, Hidenori; Maeda, Yuko; Nakagomi, Mariko; Shirakawa, Masayoshi; Watanabe, Yuichiro; Kakikawa, Taro; Numaguchi, Hirotaka; Johnson‐Levonas, Amy O.; Blaustein, Robert O.

doi:10.1016/j.atherosclerosis.2017.03.009

Cited by 13 publications

(8 citation statements)

References 20 publications

(27 reference statements)

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“…Furthermore, while the sample sizes of LDL-C and HDL-C GWASs were substantially smaller in East Asians (n = 146,492) compared to European (n = 1,320,016) participants, colocalization analysis clearly indicated the HDL-C signal was shared across ancestries and the LDL-C CETP signal was isolated to European ancestry groups, suggesting that these findings do not simply reflect a lack of sample size, in which case the posterior probabilities would follow a uniform distribution. Nevertheless, randomised controlled trials of anacetrapib conducted in Japanese individuals showed a decreasing effect of CETP inhibition on LDL-C concentration: −38.0% (95%CI −42.4; −33.7) change from baseline 18 , which did not meaningfully differ from the effect observed in European trial participants. This suggests that the lack of LDL-C signal observed in our study, as well as that of Millwood et al, is likely limited to the genetic effects of CETP variants on LDL-C, and does not reflect a fundamental difference in the biology of CETP between European and East Asian individuals.…”

Section: Discussioncontrasting

confidence: 55%

“…For both diseases, there is however limited information on the potential differences between ancestries of altered lipid metabolism or CETP metabolism specifically. Although approximately 10-30% of participants enroled in CETP-inhibitor trials are of East Asian ancestry 4,18,25 , these studies have not been designed to detect potential differences between ancestry groups, and hence the lack of observed association in these trials does not fully rule out a possible ancestry specific risk increasing effects. Furthermore, it is important to consider to what extent the difference between the effects of CETP on asthma and lung cancer reflect genetic ancestry, or whether these differences might be explained by correlated environmental factors, such as air pollution or life-style choices such as smoking.…”

Section: Discussionmentioning

confidence: 99%

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Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study

Dunca,

Chopade,

Gordillo-Marañón

et al. 2024

Nat Commun

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CETP inhibitors are a class of lipid-lowering drugs in development for treatment of coronary heart disease (CHD). Genetic studies in East Asian ancestry have interpreted the lack of CETP signal with low-density lipoprotein cholesterol (LDL-C) and lack of drug target Mendelian randomization (MR) effect on CHD as evidence that CETP inhibitors might not be effective in East Asian participants. Capitalizing on recent increases in sample size of East Asian genetic studies, we conducted a drug target MR analysis, scaled to a standard deviation increase in high-density lipoprotein cholesterol. Despite finding evidence for possible neutral effects of lower CETP levels on LDL-C, systolic blood pressure and pulse pressure in East Asians (interaction p-values < 1.6 × 10−3), effects on cardiovascular outcomes were similarly protective in both ancestry groups. In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study

Dunca,

Chopade,

Gordillo-Marañón

et al. 2024

Nat Commun

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“…A previous examination of obicetrapib in the Netherlands and Denmark which administered 10 mg obicetrapib as monotherapy and in combination with moderate intensity statins, 10 mg rosuvastatin or 20 mg atorvastatin, for 12 weeks reported LDL-C reductions of 45.3%, 63.3%, and 68.2%, respectively 10) . Since then, two phase 2 trials of 10 mg obicetrapib monotherapy administered on top of high-intensity statins, in trials that included ＜5% of participants have also found similar effects of reducing LDL-C and increasing HDL-C as in non-Japanese populations 18,19) .…”

Section: Discussionmentioning

confidence: 94%

Obicetrapib as an Adjunct to Stable Statin Therapy in Japanese Subjects: Results from a Randomized Phase 2 Trial

Harada-Shiba,

Davdison,

Ditmarsch

et al. 2024

JAT

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Aims: Obicetrapib is a highly selective cholesteryl ester transfer protein (CETP) inhibitor shown to reduce lowdensity lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), when taken as monotherapy and in combination with ezetimibe on a background of statins, in clinical trials predominantly conducted in Northern European/Caucasian participants. We characterized the efficacy, safety, and tolerability of obicetrapib within an Asian-Pacific region population. Methods: This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL. Endpoints included LDL-C, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol, apolipoproteins, TG, steady state pharmacokinetics (PK) in obicetrapib arms, safety, and tolerability.Results: In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all p＜0.0001 vs. placebo). The PK profile demonstrated near complete elimination of drug by 4 weeks. Obicetrapib was well tolerated and there were no adverse safety signals.Conclusions: All doses of obicetrapib taken as an adjunct to stable statin therapy significantly lowered atherogenic lipoprotein lipid parameters, showed near complete elimination of drug by 4 weeks, and were safe and well tolerated in a Japanese population, similar to previous studies of obicetrapib conducted in predominantly Caucasian participants.

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“…It was revealed that there was no significant decrease in the risk of revascularization in the group of CETP inhibitors versus the placebo group (RR = 0.93; 95% CI: 0.81-1.07; p = 0.30; I2 = 74%) (Supplementary Figure S5). There was also no significant difference between the three subgroups for this outcome (p = 0.53) [10,27,29,33,[35][36][37][38]40].…”

Section: Revascularizationmentioning

confidence: 84%

“…The pooled analysis revealed no significant differences in reducing the risk of said outcome between both groups (RR = 0.93; 95% CI: 0.68-1.28; p = 0.66; I2 = 31%) (Supplementary Figure S4). Running the subgroup analyses for this outcome revealed no significant difference (p = 0.40) [10,27,29,33,[35][36][37][38]40].…”

Section: Hospitalization Due To Acute Coronary Syndromementioning

confidence: 88%

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Rehman,

Yarkoni,

Ilyas

et al. 2024

JCDD

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Background: Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis’ efficacy. Methods: We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible. Primary outcomes: major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality. Secondary outcomes: stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI). Results: Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81–0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86–0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes. Conclusions: Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

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Lipid-modifying efficacy and tolerability of anacetrapib added to ongoing statin therapy in Japanese patients with dyslipidemia

Abstract: Long-term treatment with anacetrapib 100 mg substantially reduced LDL-C, increased HDL-C and was well tolerated in Japanese patients with dyslipidemia (ClinicalTrials.gov number NCT01760460).

Cited by 13 publications

References 20 publications

Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study

Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study

Obicetrapib as an Adjunct to Stable Statin Therapy in Japanese Subjects: Results from a Randomized Phase 2 Trial

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

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